NT >99th centile and cystic hygroma: Which diagnosis, which management and outcome.

OBJECTIVES: To evaluate the prevalence of chromosomal anomalies in fetuses affected by increased nuchal translucency(iNT >99Th centile), cystic hygroma (CH) and cases progressing to fetal hydrops (NIHF) in order to correlate this result to prognosis and perinatal fetal outcomes, improving patient's counseling. METHODS: From January 2020 to December 2023, first trimester screening according to FMF criteria were performed in "Maternal fetal medicine Unit" of Foggia's hospital. We studied and collected clinical data of fetuses affected by nuchal translucency >99th centile (iNT), CH and cases progressing to Fetal Hydrops (non-immune fetal hydrop, NIFH). In these selected cases, we evaluated fetal Karyotype to demonstrate the presence of chromosomal abnormalities, associated to fetal structural anomalies and different pregnancy outcome. RESULTS: We have evaluated 45 cases of iNT, CH, and NIFH, identified by ultrasound during first trimester screening. Of these 45 pregnant women, four were lost to follow-up. Of the 41 pregnancies, 20 cases (48.8%) delivered at our division with newborns discharged in good health. Of the 21 patients (51.2%) who miscarried, only two miscarried spontaneously; the other 19 decided on a medical termination of pregnancy (MTP). The 19 patients who decided for MTP showed genetic abnormalities and/or malformation. The 20 cases of fetuses discharged as healthy newborns were enrolled with the following diagnoses: 5 had a diagnosis of CH (20% of cases), 1 case of NIFH (5% of cases), and 14 of iNT (75% of cases). All these fetuses had a normal karyotype and no major malformations. CONCLUSIONS: Isolated CH diagnosis is more frequent than described in Literature (5 cases out of 12: 41.7%) and their prognosis are better than previously described, with the same outcomes of fetuses with iNT without associated anomalies. The possibility of early diagnosis of chromosomal anomalies, associated malformations or the evolution into hydrops is essential for a complete consultation.

Outcome of twin-twin transfusion syndrome according to Quintero stage of disease: systematic review and meta-analysis.

OBJECTIVES: To report the outcome of pregnancies complicated by twin-twin transfusion syndrome (TTTS) according to Quintero stage. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for studies reporting the outcome of pregnancies complicated by TTTS stratified according to Quintero stage (I-V). The primary outcome was fetal survival rate according to Quintero stage. Secondary outcomes were gestational age at birth, preterm birth (PTB) before 34, 32 and 28 weeks' gestation and neonatal morbidity. Outcomes are reported according to the different management options (expectant management, laser therapy or amnioreduction) for pregnancies with Stage-I TTTS. Only cases treated with laser therapy were considered for those with Stages-II-IV TTTS and only cases managed expectantly were considered for those with Stage-V TTTS. Random-effects head-to-head meta-analysis was used to analyze the extracted data. RESULTS: Twenty-six studies (2699 twin pregnancies) were included. Overall, 610 (22.6%) pregnancies were diagnosed with Quintero stage-I TTTS, 692 (25.6%) were Stage II, 1146 (42.5%) were Stage III, 247 (9.2%) were Stage IV and four (0.1%) were Stage V. Survival of at least one twin occurred in 86.9% (95% CI, 84.0-89.7%) (456/552) of pregnancies with Stage-I, in 85% (95% CI, 79.1-90.1%) (514/590) of those with Stage-II, in 81.5% (95% CI, 76.6-86.0%) (875/1040) of those with Stage-III, in 82.8% (95% CI, 73.6-90.4%) (172/205) of those with Stage-IV and in 54.6% (95% CI, 24.8-82.6%) (5/9) of those with Stage-V TTTS. The rate of a pregnancy with no survivor was 11.8% (95% CI, 8.4-15.8%) (69/564) in those with Stage-I, 15.0% (95% CI, 9.9-20.9%) (76/590) in those with Stage-II, 18.6% (95% CI, 14.2-23.4%) (165/1040) in those with Stage-III, 17.2% (95% CI, 9.6-26.4%) (33/205) in those with Stage-IV and in 45.4% (95% CI, 17.4-75.2%) (4/9) in those with Stage-V TTTS. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS. Overall, the incidence of PTB and neonatal morbidity increased as the severity of TTTS increased, but data on these two outcomes were limited by the small sample size of the included studies. When stratifying the analysis of pregnancies with Stage-I TTTS according to the type of intervention, the rate of fetal survival of at least one twin was 84.9% (95% CI, 70.4-95.1%) (94/112) in cases managed expectantly, 86.7% (95% CI, 82.6-90.4%) (249/285) in those undergoing laser therapy and 92.2% (95% CI, 84.2-97.6%) (56/60) in those after amnioreduction, while the rate of double survival was 67.9% (95% CI, 57.0-77.9%) (73/108), 69.7% (95% CI, 61.6-77.1%) (203/285) and 80.8% (95% CI, 62.0-94.2%) (49/60), respectively. CONCLUSIONS: Overall survival in monochorionic diamniotic pregnancies affected by TTTS is higher for earlier Quintero stages (I and II), but fetal survival rates are moderately high even in those with Stage-III or -IV TTTS when treated with laser therapy. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS treated with laser and expectant management, respectively. In pregnancies affected by Stage-I TTTS, amnioreduction was associated with slightly higher survival compared with laser therapy and expectant management, although these findings may be confirmed only by future head-to-head randomized trials. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Resultado del síndrome de transfusión feto-fetal según el estadio de Quintero de la enfermedad: revisión sistemática y metaanálisis OBJETIVOS: Informar sobre el resultado de los embarazos complicados por el síndrome de transfusión feto-fetal (TTTS, por sus siglas en inglés) según el estadio de Quintero. MÉTODOS: Se hicieron búsquedas en las bases de datos de MEDLINE, EMBASE y CINAHL de estudios que hubieran informado sobre el resultado de embarazos complicados por TTTS, estratificados según el estadio de Quintero (I-V). El resultado primario fue la tasa de supervivencia fetal según el estadio de Quintero. Los resultados secundarios fueron la edad gestacional al nacer, el parto pretérmino (PPT) antes de las 34, 32 y 28 semanas de gestación y la morbilidad neonatal. Los resultados se reportan de acuerdo con las diferentes opciones de tratamiento (expectante, terapia de láser o amniorreducción) para los embarazos con TTTS en Estadio I. Sólo se consideraron los casos tratados con terapia de láser para aquellos con TTTS de las Etapas II-IV y sólo se consideraron los casos tratados de manera expectante para aquellos con TTTS de la Etapa V. Para analizar los datos extraídos se utilizó un metaanálisis directo de efectos aleatorios. RESULTADOS: Se incluyeron veintiséis estudios (2699 embarazos de gemelos). En total, 610 (22,6%) embarazos fueron diagnosticados con TTTS de Estadio I de Quintero, 692 (25,6%) de Estadio II, 1146 (42,5%) de Estadio III, 247 (9,2%) de Estadio IV y cuatro (0,1%) de Estadio V. La supervivencia de al menos un gemelo se produjo en el 86,9% (IC 95%, 84,0-89,7%) (456/552) de los embarazos en Estadio I, en el 85% (IC 95%, 79,1-90,1%) (514/590) de aquellos en Estadio II, en el 81,5% (IC 95%, 76,6-86,0%) (875/1040) de aquellos en Estadio-III, en el 82,8% (IC 95%, 73,6-90,4%) (172/205) de aquellos en Estadio-IV y en el 54,6% (IC 95%, 24,8-82,6%) (5/9) de aquellos en Estadio-V de TTTS. La tasa de embarazos sin supervivientes fue del 11,8% (IC 95%, 8,4-15,8%) (69/564) de aquellos en Estadio-I, 15,0% (IC 95%, 9,9-20,9%) (76/590) de aquellos en Estadio-II, 18,6% (IC 95%, 14,2-23,4%) (165/1040) de aquellos en Estadio-III, 17,2% (IC 95%, 9,6-26,4%) (33/205) de aquellos en Estadio-IV y en el 45,4% (IC 95%, 17,4-75,2%) (4/9) de aquellos en Estadio-V de TTTS. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V. En general, la incidencia de PPT y la morbilidad neonatal aumentaron a medida que se incrementó la gravedad del TTTS, pero los datos sobre estos dos resultados se vieron limitados por el pequeño tamaño de la muestra de los estudios incluidos. Al estratificar el análisis de los embarazos con TTTS en Estadio I según el tipo de tratamiento, la tasa de supervivencia fetal de al menos un gemelo fue del 84,9% (IC 95%, 70,4-95,1%) (94/112) en los casos tratados de forma expectante, del 86,7% (IC 95%, 82,6-90.4%) (249/285) en los sometidos a terapia láser y del 92,2% (IC 95%, 84,2-97,6%) (56/60) en los sometidos a amniorreducción, mientras que la tasa de supervivencia doble fue del 67,9% (IC 95%, 57,0-77,9%) (73/108), del 69,7% (IC 95%, 61,6-77,1%) (203/285) y del 80,8% (IC 95%, 62,0-94,2%) (49/60), respectivamente. CONCLUSIONES: La supervivencia en general en los embarazos biamnióticos monocoriónicos afectados por TTTS es mayor en los estadios tempranos de Quintero (I y II), pero las tasas de supervivencia fetal son moderadamente altas incluso en aquellos con TTTS en estadios III o IV cuando se tratan con terapia láser. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V tratados con láser y tratamiento expectante, respectivamente. En los embarazos afectados por TTTS en Estadio I, la amniorreducción estuvo asociada con una supervivencia ligeramente mayor en comparación con la terapia de láser y el tratamiento expectante, aunque estos hallazgos solo pueden confirmarse mediante futuros estudios aleatorizados directos. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Outcome of twin-to-twin transfusion syndrome in monochorionic monoamniotic twin pregnancy: systematic review and meta-analysis.

OBJECTIVES: To explore the outcome of monochorionic monoamniotic (MCMA) twin pregnancies affected by twin-to-twin transfusion syndrome (TTTS). METHODS: MEDLINE and EMBASE databases were searched for studies reporting the outcome of MCMA twin pregnancies complicated by TTTS. The primary outcome was intrauterine death (IUD); secondary outcomes were miscarriage, single IUD, double IUD, neonatal death (NND), perinatal death (PND), survival of at least one twin, survival of both twins and preterm birth (PTB) before 32 weeks' gestation. Outcomes were assessed in MCMA twins affected by TTTS not undergoing intervention and in those treated with amniodrainage, laser therapy or cord occlusion. Subgroup analysis was performed including cases diagnosed before 24 weeks. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Fifteen cohort studies, including 888 MCMA twin pregnancies, of which 44 were affected by TTTS, were included in the review. There was no randomized trial comparing the different management options in MCMA twin pregnancies complicated by TTTS. In cases not undergoing intervention, miscarriage occurred in 11.0% of fetuses, while the incidence of IUD, NND and PND was 25.2%, 12.2% and 31.2%, respectively. PTB complicated 50.5% of these pregnancies. In cases treated by laser surgery, the incidence of miscarriage, IUD, NND and PND was 19.6%, 27.4%, 7.4% and 35.9%, respectively, and the incidence of PTB before 32 weeks' gestation was 64.9%. In cases treated with amniodrainage, the incidence of IUD, NND and PND was 31.3%, 13.5% and 45.7% respectively, and PTB complicated 76.2% of these pregnancies. Analysis of cases undergoing cord occlusion was affected by the very small number of included cases. Miscarriage occurred in 19.2%, while there was no case of IUD or NND of the surviving twin. PTB before 32 weeks occurred in 50.0% of these cases. CONCLUSIONS: MCMA twin pregnancies complicated by TTTS are at high risk of perinatal mortality and PTB. Further studies are needed in order to elucidate the optimal type of prenatal treatment in these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Biomolecular basis related to inflammation in the pathogenesis of endometrial cancer.

OBJECTIVE: Endometrial cancer (EC) is a complex gynecological neoplasm with several clinical, histopathological and genetic features. Different hormonal, metabolic and biochemical axes are involved in pathogenesis. Obesity is a well-known risk factor for this disease and the role of local and systemic effects of adipose tissue, especially in the promotion of subclinical chronic inflammation, is an important issue. Indeed, inflammation is related to the pathogenesis of different tumors, including EC. This review aims to remark the role of obesity and inflammation in the pathogenesis of EC cancer through an exploration of the current literature. MATERIALS AND METHODS: We performed a comprehensive review of the literature through a PubMed search using key words and including English language papers looking at this topic. RESULTS: Only few authors analyzed the role of inflammatory cytokines released by adipose tissue in visceral abdominal fat depots. Tumor Necrosis Factor-α, Interleukin-6, Interleukin-1 Receptor Antagonist, Nuclear Factor-kB, Leptin, Adiponectin and C Reactive Protein were studied for cancer risk prediction models, risk stratification or targeted therapies. Furthermore, genetic studies evaluated the effect of inflammatory cytokines secreted by visceral adipocytes in the modulation of angiogenesis and signaling pathways such as PI3K/AKT/mTOR, that result altered in the pathogenesis of EC. CONCLUSIONS: The identification of inflammatory biomarkers released by adipose tissue, in the pathogenesis of EC, could be useful in improving diagnostic accuracy, identifying targets of therapy, suggesting useful lifestyle behaviors. A deeper knowledge of the genetic background of alterations in inflammatory pathway genes could better define the population exposed to a higher susceptibility to EC due to genetic polymorphisms. Future studies are needed to better understand this field.

Management of bladder endometriosis with combined transurethral and laparoscopic approach. Follow-up of pain control, quality of life, and sexual function at 12 months after surgery.

To describe the pre-surgical and post-surgical outcomes at one year in terms of recurrence of lower urinary tract symptoms, quality of life, and sexual function of a transurethral and laparoscopic combined approach in the treatment of bladder endometriosis. The au- thors performed a prospective observational study of 16 women affected by symptomatic bladder endometriosis at the University Hos- pitals of Cagliari, Padua, and Foggia. In all patients bladder nodule was excised with a transurethral and laparoscopic combined approach technique. Intensity of lower urinary tract symptoms (VAS score) were assessed pre- and post-operatively at one, six, and 12 months after surgery; quality of life (SF-36) and sexual functions (FSFI) were collected preoperatively and one year postoperatively. Operative time was 120.18 ± 15.77 minutes and mean blood loss was 65.12 ± 44.74. No intraoperative and postoperative complications and conversion laparotomy occurred. Intensity of lower urinary tract symptoms evaluated with VAS score were significantly lower after one, six, and 12 months postsurgery vs. presurgery (p < 0.001). The authors observed a significantly improvement in the quality of life and sexual functions in all patients at one year after surgery. This surgical approach is safe and simple in the treatment of bladder en- dometriosis, with low risks and optimal resolution of symptoms, and improvement of quality of life and sexual function.

Bilateral salpingo-oophorectomy and adhesiolysis with single port access laparoscopy and use of diode laser in a BRCA carrier.

Herein the authors report the first case of prophylactic bilateral salpingo-ovariectomy (BSO) in single port access laparoscopy (SPAL) with use of diode laser in a patient with BRCA1 mutation. As fimbria could be considered the site of origin for many serous carcinomas in BRCA mutation carriers, many studies are carried out to evaluate the possibility of preventing ovarian carcinoma with BSO. SPAL is a development of endoscopic surgery which further reduces invasiveness of surgical procedures. Diode laser presents a recognized precision for tissue cutting and coagulation and its use could be highly advantageous in SPAL surgery and in particular in such situations avoiding fallopian tube histology distortion and consequently improve the prognosis of BRCA carriers.

First case of prophylactic salpingectomy with single port access laparoscopy and a new diode laser in a woman with BRCA mutation.

•Single port access laparoscopy may be suggested for prophylactic salpingectomy in BRCA carriers.•Diode laser salpingectomy could preserve ovarian function as it can cut and coagulate with extreme precision and minimal thermal damage.

Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells.

BACKGROUND: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. METHODS: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. RESULTS: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. CONCLUSIONS: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Accuracy of hysteroscopy made by young residents in detecting endometrial pathologies in postmenopausal women.

PURPOSE OF INVESTIGATION: The aim of the study was to analyze the diagnostic value of hysteroscopy made by young residents in evaluating uterine cavity compared to experienced hysteroscopists with histological diagnosis as reference in postmenopausal women, with particular attention to endometrial hyperplasia and cancer. MATERIALS AND METHODS: A total of 600 postmenopausal women that underwent diagnostic hysteroscopy (DH) between January 2011 and December 2013 were evaluated. The authors compared the first 200 hysteroscopic findings of each young resident with those of seniors that supervised all the procedures, regarding the same patients. Subsequent histological evaluation was obtained by operative hysteroscopy or endometrial biopsy. Residents' and seniors' data were compared with the final histological diagnosis established by anatomopathologist. RESULTS: No adverse effects such as vaso-vagal reactions or uterine perforations in DH neither in operative hysteroscopic procedures were reported. Hysteroscopy made by residents had 60%, 9.09%, and 70.4% sensitivity (SE) and 97.1%, 98.8%, and 99.1% specificity (SP) in detecting hyperplasia without atypia, hyperplasia with atypia, and endometrial cancer, respectively. On the other hand, DH made by seniors resulted in 85%, 72.7%, and 96.3% SE and 99.8%, 99.8%, and 100% SP, in detecting the same three histological findings. CONCLUSION: Outpatient hysteroscopy made by residents at their endoscopic experience beginning has good accuracy in detecting clear endometrial malignant lesions, unlike in detecting premalignant lesion as hyperplasia with atypia. This could signify that more than 200 hysteroscopies are necessary for a resident to well recognize premalignant and malignant lesions.

Uterine leiomyosarcoma: report of three cases and review of the literature.

This is the report of three cases of unsuspected uterine leiomyosarcoma diagnosed by pathologist after hysteroscopic resection. The literature on this issue has been reviewed. Mesenchymal uterine tumors are rare malignancies, occurring in only 17 per one million women annually. The three most common variants of uterine sarcoma are endometrial stromal sarcoma, leiomyosarcoma, and malignant mixed Müllerian tumour. Less than one percent of women believed to have a leiomyoma actually have a sarcoma at hysterectomy. According to the authors' experience and the available literature reviewed, the removal of the whole myomatosus lesion, even if its appearance suggests a typical submucosal myoma, represents the only method to definitively rule out the presence of sarcomatous tissue.

The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models.

BACKGROUND: Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. METHODS: Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo. RESULTS: Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival. CONCLUSIONS: Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.

Laparoscopic surgical staging of endometrial cancer: does obesity influence feasibility and perioperative outcome?

AIM: Laparoscopic treatment of early-stage endometrial cancer is the gold standard to reduce perioperative morbidity. Obesity is a well-known risk factor for endometrial cancer and anesthesiological and surgical complications. The authors' aim was to examine the effect of body mass index (BMI) on perioperative parameters and complications in laparoscopically-treated patients with endometrial cancer. MATERIALS AND METHODS: A consecutive series of patients affected by endometrial cancer and their demographic and clinicopathological data were collected. Patients were divided in 41 non-obese (BMI or= 30) groups. All patients had been preoperatively evaluated with hysteroscopic procedures and toraco-abdominal computed tomography (CT) and had been submitted to laparoscopic radical hysterectomy according to Querleu-Morrow, pelvic lymphadenectomy, peritoneal washing, and bilateral adnexectomy. RESULTS: There was no statistically significant difference in blood loss, number of lymph nodes removed, and hospital stay between the groups, but there was a trend towards a lengthening of surgical time in the obese women. There were no major intraoperative and postoperative complications. DISCUSSION: This study demonstrates that laparoscopic approach is feasible and safe in obese women evaluating the anesthesiological risk.

Angiogenic and signalling proteins correlate with sensitivity to sequential treatment in renal cell cancer.

BACKGROUND: We aimed to study key signalling proteins involved in angiogenesis and proliferation on the response to inhibitors of tyrosine kinases and mammalian target of rapamycin in first- and in second-line treatment of renal cell carcinoma (RCC). METHODS: In a panel of human RCC tumours, in vitro and in nude mice, we evaluated the effect of sunitinib, sorafenib and everolimus, alone and in sequence, on tumour growth and expression of signalling proteins involved in proliferation and resistance to treatment. RESULTS: We demonstrated that, as single agents, sunitinib, sorafenib and everolimus share similar activity in inhibiting cell proliferation, signal transduction and vascular endothelial growth factor (VEGF) secretion in different RCC models, both in vitro and in tumour xenografts. Pre-treatment with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Inability by sunitinib to persistently inhibit HIF-1, VEGF and pMAPK anticipated treatment resistance in xenografted tumours. After first-line sunitinib, second-line treatment with everolimus was more effective than either sorafenib or rechallenge with sunitinib in interfering with signalling proteins, VEGF and interleukin-8, translating into a significant advantage in tumour growth inhibition and mice survival. CONCLUSION: We demonstrated that a panel of angiogenic and signalling proteins can correlate with the onset of resistance to sunitinib and the activity of everolimus in second line.

Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis.

BACKGROUND: Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors. METHODS: We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells. RESULTS: Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions. CONCLUSION: A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.

Paraneoplastic sensitive neuropathy associated with anti-hu antibodies in a neuroendocrine tumor of duodenum: a case report.

Paraneoplastic sensitive neuropathy is one of the most common presentations among a group of cancer-related disorders known as Paraneoplastic Neurological Syndromes (PNS). PNS likely have an autoimmune etiology since they have been associated with the presence of antibodies against neuronal antigens expressed by tumor cells (such as anti-Hu, anti-Ri and anti-Yo). The tumors most frequently associated with PSN and onconeural antibodies are lung cancer, lymphomas and gynaecological tumors; however, they have also been described in other tumors. We report, for the first time, a case of neuroendocrine tumor of duodenum and PNS associated with anti-Hu antibodies. Moreover, we analyze and discuss the clinical implications that PNS and anti-Hu could have in patients with tumors.

Malignant mixed müllerian tumor of the fallopian tube coincident with a primary serous carcinoma of the ovary. Case report.

Malignant mixed müllerian tumors are very rare neoplasms of the fallopian tube, and treatment is not well defined. A case of malignant mixed müllerian tumor of the tube concomitant with a primary serous carcinoma of the ovary is reported. It was unclear if there were two distinct neoplasms in the same patient, or if it was a single tumor with a sarcomatous fallopian conversion of the serous component, as described for some recurrent ovarian carcinomas. Chemotherapy for ovarian carcinoma with intraperitoneal metastasis was performed, with about a three-year interval-free period of disease, as could be expected for ovarian carcinomas at the same stage. Such coexistence of these two tumors does not afford adequate staging of the malignancy. Therapy for the very rare cases similar to the one reported here needs to be improved.

Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients are more predisposed than HIV-negative women to develop squamous intraepithelial lesions (SIL) of the uterine cervix, and cervical dysplasia may be of higher grade in HIV-positive women than in HIV-negative subjects, with more extensive and multi-centric involvement of the lower genital tract by human papillomavirus (HPV)-associated lesions. Moreover, recurrence and progression rate of cervical intraepithelial neoplasia (CIN) is particularly higher in immunocompromised women. DESIGN: Retrospective case-control study of HIV-positive women and HIV-negative controls, all affected by low-grade SIL of the uterine cervix, treated by loop excision or followed-up without treatment. Correlation of progression and recurrence of SIL with HIV status and CD4+ count. PATIENTS: From September 1990 to October 1997, 75 HIV-positive low-grade-SIL patients, 47 treated and 28 followed-up without treatment, and 75 HIV-negative low-grade-SIL controls, 45 treated and 30 followed-up. RESULTS: Among treated patients, 17/47 (36.2%) HIV-positive and 5/45 (11.1%) controls had recurrence (P < 0.0101, O.R. = 4.53, 95% CI = 1.5-13.7), progression of untreated lesion was seen in 15/28 (53.6%) HIV-positive and 7/30 (23%) controls (P < 0.05, O.R. = 3.79, 95% CI = 1.23-11.69). The risk of recurrence or progression of low-grade SIL linked to HIV seropositivity is about 4-5 times higher in comparison with seronegative counterpart, matched for age, risk factors and lesion size. More significantly, considering the cut-off of 200 CD4+/mm(3) in HIV-positive women, 13/17 cases of recurrence (P < 0.05, O.R. = 4.88, 95% CI = 1.28-18.58) and 10/15 cases with progression (P < 0.05, O.R. = 6.67, 95% CI = 1.24-35.73) were immunocompromised (<200 CD4+/mm3), with a significant higher risk of recurrence or progression linked to immunodeficiency status. Considering time of progression or recurrence, during follow-up, Kaplan-Meier curves shows that HIV-positive status and immunodeficiency are correlated with more rapid evolution of cervical dysplasia and HPV-related lesions: comparison of recurrence in treated patients report P < 0.005 and progression in untreated P<0.05 (Mantel-Haenszel log-rank test). CONCLUSIONS: Immunological status seems to be a determinant factor in prognosis of cervical SIL, HIV-positive women affected by this lesion, even if low-grade, need more aggressive management than the immunocompetent counterpart. Strict cytologic and colposcopic screening is recommended and CD4+ count and HPV-DNA testing may be useful risk indicators. Excisional procedures are preferred, while ablative treatments or wait and see policy may expose to some risk this type of population with poor compliance to follow-up.

Operative office hysteroscopy without anesthesia: analysis of 4863 cases performed with mechanical instruments.

STUDY OBJECTIVE: To evaluate the efficacy of, and patients' satisfaction with, office hysteroscopic treatment of benign intrauterine pathologies using 5F hysteroscopic instruments. DESIGN: Observational clinical study (Canadian Task Force classification II). SETTING: University center. PATIENTS: Four thousand eight hundred sixty-three (4863) women. INTERVENTION: Office hysteroscopy without analgesia or anesthesia. MEASUREMENTS AND MAIN RESULTS: We used 5F mechanical instruments (scissors, grasping forceps) to treat cervical and endometrial polyps ranging between 0.2 and 3.7 cm, as well as intrauterine adhesions and anatomic impediments. From 71.9% to 93.5% of women underwent the procedure without discomfort for all pathologies treated except endometrial polyps larger than the internal cervical os, for which 63.6% experienced low or moderate pain. At 3-month follow-up, pathology persisted in 364 patients (5.6%). CONCLUSION: Simple instruments enable us to perform many operative procedures in an office setting with excellent patient satisfaction, provided that the indications are correct.